Correlation between Prostate-Specific Antigen Kinetics and Overall Survival in Abiraterone Acetate-Treated Castration-Resistant Prostate Cancer Patients
Menée à partir des données de deux essais de phase III évaluant l'acétate d’abiratérone et incluant au total 2 265 patients atteints d'un cancer métastatique de la prostate résistant à la castration, cette étude met en évidence l'intérêt d'analyser l'évolution du niveau sérique de l'Antigène Prostatique Spécifique à la place de la survie globale pour déterminer le bénéfice clinique de l'acétate d’abiratérone, indépendamment du type de chimiothérapie reçue
Purpose : We constructed a biomarker-survival modeling framework to explore the relationship between prostate-specific antigen (PSA) kinetics and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients following oral administration of 1,000 mg/d of abiraterone acetate (AA).
Experimental Design : The PSA-survival modeling framework was based on data from two phase III studies, COU-AA-301 (chemotherapy-pretreated, n = 1,184) and COU-AA-302 (chemotherapy-naïve, n = 1,081), and included a mixed-effects tumor growth inhibition model and a Cox proportional hazards survival model.
Results : The effect of AA on PSA kinetics was significant (P < 0.0001) and comparable between the chemotherapy-naïve and -pretreated patients. PSA kinetics (e.g., PSA nadir, PSA response rate [≥30, 50, and 90%], time to PSA progression, PSA doubling time [PSADT]) were highly associated with OS in both populations. The model-based post-treatment PSADT had the strongest association with OS (hazard ratio ~0.9 in both populations). The models could accurately predict survival outcomes. After adjusting for PSA kinetic end points, the treatment effect of AA on survival was no longer statistically significant in both studies, and the Prentice criteria of surrogacy were met for the PSA kinetic end points. A strong correlation was also observed between PSA and radiographic progression-free survival.
Conclusions : The analysis revealed a consistent treatment effect of AA on PSA kinetics and strong associations between PSA kinetics and OS in chemotherapy-pretreated and -naïve patients, thereby providing a rationale to consider PSA kinetics as surrogacy end points to indicate clinical benefit in AA-treated patients with mCRPC regardless of chemotherapy treatment.
Clinical Cancer Research , résumé, 2015